Project Summary/Abstract Ethical concerns raised from both current and historically controversial psychosurgeries are driving disparities in accessibility to emerging BRAIN Initiative technology for those with severe, disabling, chronic mental illness like individuals with treatment-refractory schizophrenia/schizoaffective disorder (TRS). The overall goal of this proposal is to investigate core ethical principles to improve transparency, accessibility and safety of BRAIN Initiative clinical trials requiring neurosurgical intervention in patients with debilitating treatment-refractory disorders in urgent need of effective novel interventions. The focus is on the three core ethical principles of the Belmont Report, respect for persons, beneficence and justice. Respect for persons is addressed in Aim 1 to thoroughly assess each TRS individual?s competence for research participation based on their ability to understand and appreciate advanced BRAIN therapy, to reason about whether the trial is a good opportunity for them or not and to express their choice about participation using a validated assessment. Beneficence is addressed in Aim 2 to improve safety by investigating disease specific surgical risks in two ways. First, surgical risk will be assessed across 14 populations being considered for BRAIN Initiative clinical trials by using health research networks to determine the prevalence of known surgical risk factors, surgery-related morbidity and mortality. Secondly, we will perform individualized risk-benefit analyses for advanced BRAIN Initiative therapeutic deep brain stimulation (DBS) technology requiring neurosurgical insertion of the DBS device. Surgical risk for DBS surgery will be based on a survey of health-related predictors validated for surgical risk assessment. Justice will be addressed in Aim 3 to improve accessibility and feasibility of BRAIN Initiative clinical trials in severely disabling disorders, like schizophrenia one of the most disabling disorders worldwide, by reducing symptom severity inclusion criteria. For BRAIN Initiative clinical trials requiring DBS neurosurgery, new symptom severity inclusion criteria will be based on having a similar health-related decrease in quality of life as patients who are currently undergoing DBS as a standard of care therapy, those with treatment-refractory Parkinson?s disease. The fundamental premise supporting this proposed investigation is that there are TRS patients who meet experimental DBS clinical trial criteria including a sufficiently poor quality of life due to untreated symptoms to warrant the risks of experimental DBS neurosurgery. Through empirical investigation, we will explore the ethical implications of excluding individuals based on their capacity to consent (Aim 1), surgical risks (Aim 2), and severity of symptoms (Aim 3) for a planned BRAIN Initiative clinical trial to treat TRS. Successful completion of the proposed Aims is expected to revolutionize our understanding of how to overcome research disparities among severely disabled individuals by improving transparency, accessibility, and safety of BRAIN Initiative clinical trials.